Cancer is a major cause of death; for example, renal cancer is an important contributor to morbidity and mortality. Current therapies are lacking due to incomplete therapeutic responses and potential adverse side effects, so new therapies are always sought after (Ratanyake et al., Organic Letters 2008, 11, 1, 57-60). Attempts have been made to identify and isolate medicinal products for cancer treatment from plant materials. For example, a large number of Phyllanthus species have been found in tropical and subtropical regions of the world and some have been used in traditional medicines. Englerin A and englerin B have been isolated and purified from the root bark and stem bark of the plant Phyllanthus engleri Pax (Euphorbiaceae). Since then, englerin compounds and derivatives thereof have been studied as potential therapeutics. See, e.g., International Patent Application WO 2013/106226, International Patent Application WO 2014/078350, International Patent Application WO 2012/084267, Radtke et al., Angew. Chem. Int. Ed. 2011, 50, 3998, 49, 3517-3519, Nicolaou et al., J. Am. Chem. Soc. 2010, 132, 8219-8222, Akee et al., J. Nat. Prod. 2012, 75, 459-463, Xu et al., Chem. Asian J. 2012, 7, 1052-1060, and Chan et al., Chem. Med. Chem. 2011, 6(3), 420-423.
In one possible mechanism, englerin compounds are believed to bind to and activate protein kinase C theta (PKCθ), an isoform found in T cells, muscle, and kidney cancers. The ability to stimulate PKCθ by englerin compounds leads to, e.g., cell cytotoxicity, insulin inhibition, and selective activation of viral replication in T cells. See, e.g., International Patent Application WO 2014/078350 and Sourbier et al., Cancer Cell, 2013, 23(2), 228-337. In another possible mechanism, it is contemplated that englerin A activates transient receptor potential canonical (TRPC) ion channels on kidney cancer cell surfaces, thereby increasing the influx of Ca2+ and killing the cancer cells (Akbulut et al., Angew. Chem. Int. Ed. 2015, 54, 3787-3791). It is further speculated that TRPC proteins and PKCθ may interact with one another but the specific mechanism of interaction is not yet known.
Thus, there continues to be an unmet need to identify novel englerin derivatives to produce treatments for diseases associated with PKCθ and/or calcium ion channel proteins, such as cancer, particularly renal cancer, and diabetes.